1.2.3- Triazine with enamines

Scheme 73 General scheme for cycloaddition of triazines with enamines...

Triazines on reaction with enamines followed by loss of a nitrogen from the intermediates give pyridine derivatives (85H2789) (Scheme 56). The reaction of 1,3,5-triazine with enamine and enaminoester hydrochlorides in acetonitrile leads to mixtures containing pyrimidines and pyridines... 

The [4+2] discoimection is a common approach for the synthesis of pyridines. Lipihska has presented an extensive report of Diels-Alder-retro-Diels-Alder reactions of 1,2,4-triazines with enamines to produce cycloalkylpyridines 05T8148>. Triazines have been used as efficient... 

Also, theoretical considerations of the FMO interactions have been performed in order to explain the regioselec-tivity observed in the Diels-Alder reaction of 5-acetyl-3-methylthio-l,2,4-triazine with enamines <2005T8148>. 

Given the pedigree of the reaction of 1,2,4-triazines with enamines, this review will highlight only a few recent uses to exemplify the... 

In an approach to the AB rings of rubrolone 65, Boger examined the use of oxazinones as a replacement for triazines. Reaction of l,3-oxazin-6-one 66 with enamines 67 produced the corresponding pyridines 70. The reaction proceeds in a manner analogous to the triazines however, instead of losing nitrogen, these systems lose CO2 via the intermediate bicyclo[2.2.2]octanes 68. The resultant 69 then loses pyrrolidine as in the triazine example. 

The DA reaction of 5-acetyl-3-methylthio-1,2,4-triazine with cyclic enamines has been used in the total synthesis of new indazolo[2,3-a]quinolizine alkaloids <06T5736>. 

The 1,2,4-triazine ring is an ambident electrophile, and reacts with enamine-type nucleophiles. For example, addition of enamine 78 to a solution of triazine 77 in acetic anhydride furnished the pyrrolotriazine 31 (Equation 24) <2003TL2421>. 

Pyridine unnelatum. 1,2,4-Triazine can function as a reactive azadicnc in Diels-Aider reactions with enamines, particularly pyrrolidine enamines, to form substituted pyridines. 

Inverse electron demand Diels-Alder/retro-Diels-Alder-type reactions, of di- and especially poly-azines with electron-rich dienophiles, interconvert six-membered rings. 1,2,4-Triazines react with enamines and enol ethers to give pyridines (Scheme 76) (CHEC-n(5)242). 

Alternative one-pot [4+2] cycloadditions producing highly-substituted pyridines have also been reported. For example, a practical and effective procedure adaptable to preparative scale utilizes silica gel to facilitate the elimination-aromatization of dihydropyridines, as shown below <07SL2217>. Substituted and unsubstituted 1,2,4-triazines 21 react with enamines, derived from pyrrolidine 22, and substituted ketones 23, to form highly substituted pyridines 24 in good to excellent yields. 

The unusual reaction of JV-haloamidines with enamines to form 1,4-dihydro-1,3,5-triazines (164) was investigated and a possible mechanism suggested [Eq. (79)].262... 

Intermediates 2Q being 1, 5-h -electrophiles react with ammonia to give 1,2,4-triazines 21. These electron-poor azadienes give with enamines the corresponding CF3- pyridines 22 via a loss of nitrogen (Scheme 47). 

Treatment of 1,2,3-triazines 1 with enamines afforded pyridines 2. This reaction has been used for the synthesis of a number of alkaloids.103,286-290 The influence of solvent and temperature on the orientation of the two reactants has been studied.286... 

The dominant influence of secondary orbital interactions is apparent in the reaction of methyl cyclopenta[e]-l,2,4-triazine-3-carboxylate with enamines from 3,4-dihydronaphthalen-1 (2//)-or -2(l/f)-ones. In the case of the 3,4-dihydronaphthalen-2-amine the fused pyridine 24 is obtained directly using the 3,4-dihydronaphthalen-l-amine the dihydropyridine is isolated, but can be oxidized to give the aromatic pyridine 25 derivative via a Cope elimination.403... 

In addition to 1,2,4-triazines condensed with carbocycles, 1,2,4-triazines condensed with heterocycles can also be used as dienes with inverse electron demand in Diels-Alder reactions. Thus, it has been shown that pyrimido[4,5-e]-1,2,4-triazines react with enamines to yield pyrido[2,3-tflpyrimidines 29 (5-deazapteridines).415... 

On treatment of compounds containing active C-H bonds with 1,3,5-triazine (1), enamines 11 and 12 are usually the first isolable products. In order to isolate such compounds, the reactions are preferably conducted in the absence of a basic condensing agent.18... 

Thermolysis of 1,2,4-triazines with a side-chain terminal nitrile group leads to the formation of condensed pyrazines <89JOCl245>. This reaction involves cycloaddition of the nitrile dienophile across C-3 and C-6 of the 1,2,4-triazine followed by aromatization of the intermediate cycloadduct by extrusion of the N—N bridge. As a typical example, the 5,6-diphenyl-1,2,4-triazine (167) is fused under nitrogen at 225-235°C to form the condensed pyrazine (168) in 71% yield (Equation (21)). Intermolecular cyclization of oxadiazinones with enamines also yields condensed pyrazines. The bicyclic intermediates lose carbon dioxide to generate 1,4-diazadienes, which aromatize to the... 

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